Genomic medicine provides potential for novel diagnostic targets and therapeutic solutions. As mutations in human genes are identified and associated with Neurodevelopmental disease, transgenic animal models offer an opportunity to invasively study the mutant gene and its role in the pathophysiology of the disease. We have previously reported the first mutation in type 2 vesicular monoamine transporter (VMAT2), causing an infantile Parkinsonism phenotype Parkinsonism-dystonia-2 (PKDYS2) (OMIM 618049)¹. Over the past decade, several additional mutations have been identified in VMAT2, giving rise to a broad phenotype spectrum and variable responses to treatment. Here, we characterize the disease's first viable transgenic mouse model and also analyze the molecular impact of the VMAT2 mutations in silico to understand the pathophysiology better and potentially improve treatment approaches.

We correlated the VMAT2 structural changes due to mutations with phenotypes. We found that there is a clear genotype-phenotype correlation, and this aids in guiding clinical decisions, enhancing patient outcomes, gaining an understanding of pathophysiology, and developing personalized treatment protocols. This work that includes  animal model generation, behavioral characterization, and protein structure-phenotype analysis, advances our understanding of the disease and provides insights for creating personalized management protocols for this, and possibly other, neurodevelopmental disorders affecting neurotransmission.

References:

Rilstone JJ, Alkhater, R. A., & Minassian, B. A. Brain dopamine-serotonin vesicular transport disease and its treatment. The New England journal of medicine. 2013;368(6):543-550.